Clinical bracket failure rates between different bonding techniques: a systematic review and meta-analysis

Summary Background Bracket failure increases the treatment time of orthodontic therapy and burdens patients with unnecessary costs, increased chair time, and possible new appointments. Objective To compare the bond failures of different orthodontic materials based on the results of available clinical studies. Search methods A systematic search of clinical trials was performed in the Cochrane, Embase, and Pubmed databases with no limitations. The list of investigated techniques contained conventional acid-etch primer (CM-AEP), self-etch primer (SEP), self-cure resin (SCR), and simple or resin-modified glass ionomer (RM-GIC) materials and procedures. Selection criteria Clinical studies reporting the failure rate of bonded brackets after using direct adhesive techniques on buccal sites of healthy teeth were included. Data collection and analysis Bracket failure rates from eligible studies were extracted by two authors independently. Risk ratios (RRs) were pooled using the random-effects model with DerSimonian–Laird estimation. Results Thirty-four publications, involving 1221 patients, were included. Our meta-analysis revealed no significant difference in the risk of bracket failures between SEP and CM-AEP. After 6, 12, and 18 months of bonding, the values of RR were 1.04 [95% confidence interval (CI), 0.67–1.61], 1.37 (95% CI, 0.98–1.92), and 0.93 (95% CI, 0.72–1.20), respectively. At 18 months, bracket failure was 4.9 and 5.2% for SEP and CM-AEP, respectively. Heterogeneity was good or moderate (I2 < 42.2%). The results of RM-GIC at 12 months indicated a 57% lower risk of bracket failure using SCR as compared with RM-GIC (RR: 0.38; 95% CI, 0.24–0.61). At 18 months, bracket failures for SCR and RM-GIC were 15.8 and 36.6%, respectively (RR: 0.44; 95% CI, 0.37–0.52, I2 = 78.9%), demonstrating three to six times higher failure rate than in the case of etching primer applications. Limitations A major limitation of the present work is that the included clinical trials, with no exceptions, showed variable levels of risk of bias. Another possible problem affecting the outcome is the difference between the clustering effects of the split mouth and the parallel group bracket allocation methods. Conclusions and implications The results revealed no significant difference between SEP and CM-AEP up to 18 months after application. RM-GIC had much worse failure rates than acid-etching methods; additionally, the superiority of SCR over RM-GIC was evident, indicating strong clinical relevance. Registration Prospero with CRD42020163362.


Introduction
Since the introduction of orthodontic treatment using directly bonded brackets on enamel, which replaced the multiband type of fixed appliance, new technologies (e.g. involving the moisture and technique sensitivity of bonding materials) have followed the old methods. While the biggest challenges of legacy therapies were the time-consuming separation of teeth, the application of bands, and the closure of interproximal spaces, newly applied direct bonding has the disadvantage of possible failure during treatment (1). Additionally, accidental debonding of brackets increases treatment time and costs (2,3). Furthermore, the rebonding procedures may increase the risk of possible redundant damage to the enamel (4).
During the development of orthodontic bonding materials, developers need to keep in mind the different expectations of practitioners. The bond strength needs to combat the traction of archwires and the forces of occlusion and mastication (5). On the other hand, the removal of brackets at the end of treatment needs to be easy, without side-effects (6). Adequate curing time and simplicity of technique are still important requirements (1).
The introduction of visible-light-cured composite materials resulted in a breakthrough in modern bracket bonding. They shortened the polymerization time, and the clinician is able to directly induce photopolymerization in contrast to the catalyst-or liquid activator-based self-cure techniques. The aspirations to further reduce chair time initiated the appearance of adhesive precoated brackets which do not require manual application of a composite to the bracket base (7). The combination of etching and priming with a self-etching primer (SEP) simplified bracket bonding and excluded the acid-etch stage of the conventional process of acid-etching primers (CM-AEP) (8). Studies that evaluated the chair time length found it significantly faster to use SEP compared with CM-AEP (9)(10)(11).
An alternative material for bracket bonding is glass ionomer. After its introduction by Wilson and Kent in 1972 (12), investigators started to study the orthodontic application of this material. Despite adverse properties such as fluoride release and adhesion to both enamel and metals, the introduction of a resin-modified light-curable version of glass ionomer broadened its indication area (13). Due to the contradictory results, it is used in orthodontics mainly for banding and bonding on wet surfaces (1).
Apparently, there is a high number of randomized and non-randomized clinical trials investigating bracket failure of orthodontic bonding materials, but most of them have relatively small sample sizes, and their outcomes were quite variable and heterogeneous. To combat the weaknesses of individual clinical studies, three meta-analyses attempted to extend our knowledge of evidence-based orthodontics (14)(15)(16) by comparing etching based techniques (14,16) in one hand, and resin and glass ionomer-based methods on the other hand (15,17) in separate meta-analyses. Unfortunately, those already published meta-analyses did not include all available studies on bracket failure and yielded contradictory results. In addition, they did not investigate the time dependency of bracket failure either, even though this is a very important aspect of potential failures since bonded brackets are intended to remain in place in the patient's mouth for a long period of time.
Therefore, the objective of the present meta-analysis and systematic review was to quantitatively and qualitatively analyse the time dependence of bracket failure, synthesizing the results of all available clinical studies to further increase the precision and statistical power of presently available evidence. According to our null hypothesis, there were no significant differences in the bracket failure rates of different orthodontic bonding techniques. We statistically compared the results of the SEP technique with the CM-AEP technique after 6, 12, and more than 18 months of orthodontic treatment, and also of self-cure resin (SCR) with RM-GIC applications after 12and 18-month follow-up periods.

Eligibility criteria review
This meta-analysis was reported according to the PRISMA 2020 statement, an updated guideline for reporting systematic reviews (18). The PRISMA checklist for our work is available in Supplementary Tables 1 and 2. It was registered in Prospero (International prospective register of systematic reviews) at the 01/06/2020 study selection with the ID number CRD42020163362.
Due to the large amount of data, the list of outcomes originally registered in Prospero was narrowed to bracket failure, while bonding time, Adhesive Remnant Index (ARI), and demineralization have not been processed statistically in this paper. Additionally, subgroup analyses were considered when the number of included studies permitted.

Eligibility and selection criteria
According to the PICO format, the following clinical question was formulated: Are there differences in bracket failure rate with one-step/two-step bonding procedures and applications of glass ionomer cements? The framework contained the following components: Population-patients with intact teeth, without prosthodontic restorations, who needed to undergo an orthodontic direct bonding procedure; Intervention and Comparison-comparison of multiple procedures, such as self-etching or conventional etching methods, light-curable or self-cured composite, glass ionomer or resin-modified glass ionomer materials, uncoated or adhesive precoated brackets; and Outcome-the failure rate of brackets.
Inclusion and exclusion criteria: clinical studies [randomized controlled trials (RCTs), non-randomized controlled trials (NRCTs), and controlled before-after studies] which analysed the failure rate of bonded brackets after using different direct adhesive techniques (including both precoated and operator coated brackets) on buccal sites of healthy teeth met the eligibility criteria for inclusion. Both split-mouth (S-M) and parallel-group (P-G) study designs have been accepted. But in this case we formed subgroups of the investigations using the two study designs. Publications that applied banded attachments, indirect orthodontic bonding techniques, or tested in vitro shear bond strength fulfilled the exclusion criteria.
Search results were handled with the help of Mendeley reference management software. Duplicated references were removed, and the remaining records were examined individually by two authors (CD and LMC). The primary method of selection was based on a check of the publication's title and abstract, followed by full-text assessments of studies that passed the previous stage. Disagreements between authors were resolved either by discussion or by consultation with a third author (GV).

Data extraction
Data extraction was performed by the two authors (CD and LMC) using a preconstructed Excel table. The following pieces of information were collected: name of first author, publication year, study design (S-M/P-G), follow-up period, number of participants, gender distribution, age, bracket type, involved techniques of intervention and comparison, and outcomes (bracket failure, bonding time, ARI). In cases of disagreement, the reviewers relied on the opinion of a third author (GV).

Risk-of-bias assessment and certainty of evidence
Based on the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions, bias evaluations were performed using the revised Cochrane risk-of-bias tool (RoB 2) for randomized trials (19) and the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) for non-randomized trials (20). The eligible randomized studies were rated as either 1. low risk of bias, 2. some concerns, or 3. high risk of bias, across the following domains: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported results. Authors rated the overall bias as low risk if more than three categories were rated as having a low risk of bias and the remaining two had some concerns; in other cases of concern variations without marks of high risk, publications were marked as having some concerns in the overall evaluation. Non-randomized studies were assessed on bias due to confounding, selection, classification on interventions, deviations from intended interventions, missing data, outcome measurement, and reported results.
The evaluation with both methods was undertaken independently by two reviewers (CD and LMC) and possible discrepancies were resolved by discussion or the intervention of third author (GV).
We used the Grading of Recommendations Assessment, Development, and Evaluation approach to assessing the certainty of evidence (21). The evaluation of each assessment criteria for each outcome and comparison was made by the above mentioned reviewers with third-party arbitration.

Statistical analysis
We provided summaries of intervention effects for each study by calculating risk ratios (RRs) for our dichotomous outcomes using the Stata 11 SE software (StataCorp LLC, College Station, Texas, USA). RRs were pooled using the random-effects model with DerSimonian-Laird estimation and displayed on forest plots. Summary RR estimation, P value, and 95% confidence interval (CI) have been calculated. Statistical heterogeneity was analysed by calculating prediction intervals, I 2 statistics and the χ 2 tests to acquire probability values; P < 0.1 was defined to indicate significant I 2 values. The minimum number of studies for performing a meta-analysis was two. As the number of eligible studies was high enough, we were able to test the presence of publication bias by creating funnel plots and performing Egger's tests. Subgroup analyses for different study designs (RCTs and NRCTs) and bracket allocation methods (S-M and P-G) were also performed. The only limitation to create subgroups was the presence of at least two studies in each statistical group.

Systematic search and selection
A total of 6138 records were identified through database searching. After removing duplicates, 5662 articles were screened. During the screening process, 5533 articles were excluded and only 129 were considered eligible for fulltext assessment. Of these publications and after exclusions, 80 studies were included in the qualitative and 34 in the quantitative syntheses (8)(9)(10)(11). The selection process is shown in Figure 1. Reasons for the exclusion of individual studies in the full-text assessment are detailed in Supplementary Table 4.

Description of excluded studies
The studies which did not meet the expectations of inclusion criteria were definitively excluded. The presence of different examined outcomes, inadequate study design, or indirect bonding technique was the common reasons for exclusion (Supplementary Table 4). A number of studies were included in the qualitative but not in the quantitative analysis as in several cases there was an insufficient number of studies having the same outcome to perform a meta-analysis on the records. These investigations were only presented in the part of systematic review of this paper (Supplementary Document 1).

Description of included studies
The majority of included studies in the quantitative synthesis were RCT. Based on the bonding technique and the materials used, they could be organized into distinct groups. Articles that investigated the bond failure involving the SEP or CM-AEP techniques with light-curable composite were classified into 6-, 12-, and over 18-month groups. The results of studies of SCR compared with glass ionomer cements (GICs) were categorized as per their follow-up periods into 12-and 18-month groups. In these groups, we found the survival results of 6599 brackets bonded with SEP, 6570 with CM-AEP, 4029 with SCR, and 4123 cemented with GIC. The characteristics and detailed descriptions of the included studies are shown in Table 1.
Patients selected for the trials represented both sexes, ranging from 10 to 21 years of age. All participants involved in  the clinical trials needed orthodontic treatment. The presence of direct and indirect restorations on buccal surfaces, congenital enamel defects, and caries constituted exclusion criteria. All authors ignored the categorization of gender, age, and race-related properties. In all studies except for three trials, the authors recognized or published no contradictory information about the inclusion of all types of orthodontic malocclusion cases. One study involved only non-extraction Class I malocclusion cases (24), another excluded Class III cases with non-balanced extractions (11), and the third did not consider patients with Class III or openbite cases (45). The allocation of brackets was predominantly based on S-M design. In principle, quadrants assigned to each adhesive or bonding technique were consequently alternated in the mouth. Thus, the same participant was involved equally in the intervention and in the comparison group. In a few exceptions, the patients were distributed in one of the groups, receiving brackets with the same protocol in all quadrants (P-G or whole-mouth design) (8,39,40).
The installation of the orthodontic appliances started with a pumice-based mechanical cleaning of the teeth. Ireland and Sherriff also examined the effect of leaving on the initial prophylaxis on the failure rate of brackets (44). Other authors did not provide sufficient data on this topic (38,40,48).
The application of acid to the enamel of teeth was the next phase of tooth preparation before bracket bonding. In the case of CM-AEP, the vast majority of studies used 37% phosphoric acid. Only one clinical trial reported the use of 30% phosphoric acid (39), while some other authors did not mention the concentration (34,38,40,46,51). The described conditioning time varied in different articles from 15, 20, 30 to 60 seconds. Some papers reported rubbing the enamel surface for 3, 3-5, 5, 10-15, or 20 seconds, and then applying a gentle air jet. In some studies (33,34,36,40), the application of GIC preceded the application of polyacrylic conditioner for 10 seconds, and one author reported the use of 37% phosphoric acid for 60 seconds (37). In the remainder of the clinical trials, the protocol did not include or mention acid treatment before the use of the GIC (24,31,32,38,39,42,44).
Except for one-stage SEP and GIC procedures, the next step during the orthodontic process was the application of different types of primers. The placement of an adhesive on the base of new, uncoated brackets was followed by their direct positioning by the clinician on the labial tooth surface. The light-curing time of resin-based materials in each interspace was predominantly 20 seconds. One study reported 10 seconds (48) and some authors also applied the light from the gingival, incisal, or oral directions, thus increasing the total exposure time per tooth (34,46).

Results of individual studies and synthesis of results
No difference in bracket failure between SEP and CM-AEP techniques after 6, 12, and more than 18 months The results were obtained from 10 studies which examined the failure rate of bonded brackets with the SEP and CM-AEP techniques, showing the evolution of performance between them after a 6-month period (9,11,22,41,45,46,(48)(49)(50)52). Our meta-analysis highlighted that 3.6% of brackets failed in the SEP and 3.6% failed in the CM-AEP group. This difference was non-significant (RR: 1.04, 95% CI, 0.67-1.61) (Figure 2 Figure 1), suggesting that leaving out one of the studies did not influence the final results. The Egger's test suggested no small-study effect (P = 0.890). After 12 months of bonding, we calculated a 4.9% failure in the SEP compared with a 3.4% failure in the CM-AEP group. The RR for failure was 1.37 (95% CI, 0.98-1.92), showing a tendency to favour the CM-AEP method (8,9,(22)(23)(24)(25)(26)45) (Figures 3 and 4). This indicated that the relative risk of bracket failure showed a tendency to become statistically significant at a moderate level of heterogeneity (overall I 2 = 42.2%). The overall estimated predictive interval was 0.58-3.27. The leave-one-out analysis was significant regarding the study of Aljubouri et al. (9). When this study was excluded, the RR was 1.49 (95% CI, 1.09-2.03), reaching a significant difference level favouring CM-AEP treatment (Supplementary Figure 2). Egger's test suggests no small-study effect (P = 0.472).
We also performed a subgroup analysis to see the difference of S-M and P-G designs separately on the outcome of 12 months studies in bracket failure ( Figure 3). We observed greatly overlapping intervals with very similar means without showing any tendency of significant difference between the S-M (RR: 1.43; 95% CI, 0.80-2.53) and the P-G (RR: 1.28; 95% CI, 0.88-1.86). The relative heterogeneity was lower in the studies which used P-G allocation (I 2 = 0.0%) in comparison with those preferred the S-M method (I 2 = 64.4%). The predictive intervals were in the range 0.11-14.64 in the P-G allocation subgroup, and 0.21-9.49 in the S-M studies.
Subgroup analysis to compare the outcome of RCTs and NRCTs were also executed to see any differences in bracket failure between SEP and CM-AEP at 12 months ( Figure 4). Again, not even a tendency for differences between NRCTs (RR: 1.10; 95% CI, 0.67-1.60) and RCTs (RR: 1.47; 95% CI, 0.94-2.29) could be detected. But the relative heterogeneity was lower in NRCTs (I 2 = 0.0%) in comparison with RCTs (I 2 = 53.9%). The predictive interval of NRCTs indicating the absolute heterogeneity could not be estimated due to the number low number of NRCTs. The predictive interval for RCTs was 0.41-5.26.

Bracket failure was lower for SCR compared with RM-GIC at both 12 and 18 months
The results of 10 studies (24,(31)(32)(33)(34)(35)(36)(37)(38)(39) were synthesized by our meta-analysis comparing the differences in the bracket failure rate of SCR and GIC, and show the evolution of performance between them after 1 year. The failure rate was found to be 5.5% in the SCR group and 11.5% in the RM-GIC group. The calculated RR indicated a significant 62% lower risk of bracket failure if the bonding technique involved SCR against GIC (RR: 0.38; 95% CI, 0.24-0.61) (Figure 6). The high value of I 2 (78.9%) suggested considerable heterogeneity between investigations. The leave-one-out analysis   yielded no significant changes (Supplementary Figure 4), while Egger's test presents no small-study effect (P = 0.129).
A subgroup analysis was also performed to compare RCT and NRCT designs on the outcome at 12 months bracket failure between SCR and GIC interventions. Once more, no tendency showing a significant difference between NRCTs (RR: 0.43; 95% CI, 0.23-0.82) and RCTs (RR: 0.33; 95% CI, 0.23-0.47) were detected ( Figure 6). Importantly, the relative heterogeneity was lower for RCTs (I 2 = 0.0%) in comparison with NRCTs (I 2 = 82.3%). The predictive interval of NRCTs indicating the absolute heterogeneity was estimated to be in the range 0.06-3.30, while the interval for RCTs was 0.03-3.30.
Four studies investigating the bond failure of SCRs and GIC after 18 months were available for data pooling (40,(42)(43)(44). The results showed that in the SCR group 15.8% of the brackets failed, whereas in the RM-GIC group the figure was 36.6%. This great difference means the risk of bracket failure was 56% lower with the SCR technique compared with GIC application (RR: 0.44; 95% CI, 0.37-0.52) (Figure 7). The leave-one-out analysis resulted in no significant outcomes (Supplementary Figure 5). The predictive interval was in the range 0.33-0.57.

Qualitative analysis
The findings of studies included in the qualitative part of our paper can be found in Supplementary Text 1.

Risk-of-bias assessment and certainty of the evidence
The six randomized studies were rated to have a low risk-ofbias level (8)(9)(10)22,23,36). Although these studies presented some concerns of bias regarding blinding and selection, the randomization process was transparent and detailed. The remainder of the articles were judged to have more bias concerns. None of these studies were double blind as it was not possible to blind the operator to the bonding type during the studies. For this reason, no study could receive a higher score (Supplementary Table 5).
The non-randomized studies presented a low or moderate risk of bias. With one exception, all publications had some deficiency regarding participant selection (31). Using even and odd numbers at the level of teeth as a division method for intervention and control groups in one study was evaluated by reviewers as an attempt to reduce confounding variables. The rest of publications were evaluated to present a moderate level of confounding factors because of the lack of randomization and no intention to control patient inclusion by age, orthodontic or dental status. Results of the ROBINS-I tool for non-randomized studies can be found in Supplementary  Table 6.

Certainty of evidence
According to our statistical results, the widest range of the predictive interval (0.11-14.64) was found when CM-AEP and SEP interventions were compared in the parallel oral application subgroup at 12 months. The widest overall predictive interval was found in the CM-AEP-SEP groups at 6 months (0.35-3.08).
We found that the level of certainty was very low (SEP versus CM-AEP 6, 12 months) and low (SEP versus CM-AEP 18 months). Due to the presence of NRCTs in all three mentioned groups, the certainty level was reduced. The decrease of final certainty level was proportional with heterogeneity. The highest level of I 2 (I 2 = 78.9%) and the proportion of NRCTs were observed in SCR-RMGIC groups. Detailed results of the GRADE assessment are found in Supplementary  Table 7.   Publication bias was evaluated by funnel plot and Egger's test. The funnel diagrams are shown in Supplementary Figure  6 for the CM-AEP-SEP comparison at 6 months, and in Supplementary Figure 7 at 12 months. Due to the insufficient number of studies no funnel plot was created for CM-AEP-SEP comparison over 18 months. Supplementary Figure 8 represents the funnel plot of the SCR-RM-GIC method after 12 months. The funnel plot of SEP and CM-AEP analysis after 6 months is a symmetrical scatter plot, with no signs of publication bias. Egger's test (P = 0.890) indicates no small-study effect here. The missing dots (studies) on the funnel plot of SEP and CM-AEP after 12 months indicate that more studies are needed with increased sample size and statistical power. At 12 months Egger's test (P = 0.472) indicates no small-study effect. The funnel plot of SCR and RM-GIC after 12 months (Supplementary Figure 8) presents slight asymmetry of the plot and indicates the presence of statistical heterogeneity, however Egger's test (P = 0.129) suggests no small-study effect. Due to the limited number of studied, no funnel plot was created for SCR and RM-GIC comparison at 18 months.

Sensitivity analysis
We conducted the leave-one-out sensitivity analysis for each calculated overall estimate. In each case none of the included records to significantly alter the overall estimate if each of the records is omitted; except for the study Aljubouri et al. (9). after 12 months of bonding. When omitting this study, a significant difference was received in bracket failure between the SEP and the CM-AEP after 12 months significantly changes the estimate of the analysis to RR: 1.49 95% CI (1.10-2.03). However, after careful examination of the records, we found no particular reason to exclude the study of Aljubouri et al. from our quantitative analysis. Supplementary Figures 1-5 are the graphical representations of the leave-one-out analysis for each overall estimate.

Discussion
For decades, clinicians have constantly sought a low failure rate and single component orthodontic cements that do not require pre-treatment of the tooth surface (53). As a result, several in vitro studies and clinical trials investigated bracket survival using various materials and techniques, while attention gradually moved from GICs to adhesive materials (1). But available data are variable and still contradictory. To seek clear evidence, the meta-analyses must be performed to send clear messages to practitioners. Using this methodology, we increased the power to detect bracket failure rates of four commonly used bracket bonding techniques (SEP, CM-AEP, SCR, and RM-GIC) and to analyse the time dependence of these failures.
A previous meta-analysis by Fleming et al. in 2012 indicated that the SEP method is inferior to the CM-AEP bonding technique (14), while by Namdari et al. (16) in 2021 indicated no difference in bracket debonding between these techniques. But none of these studies investigated the time dependence of bracket failure, an important factor when we consider the considerable length of orthodontic treatments. In the present work, by including more studies and creating groups based on follow-up periods we were able to show that SEP and conventional method (CM-AEP) did not demonstrate significant difference in failure rate at either 6, 12, or 18 months after bonding. However, the sensitivity analysis indicated that exclusion of the study of Aljubouri et al. (9). significantly affected the outcome of our analysis at 12 months. In the case of exclusion the difference between the two methods became significant, favouring CM-AEP application. After in-depth analysis we decided to not to exclude this study from our analysis, since we could not reveal any substantial difference in methodology between this work (9)  Taken together, our results suggest that the SEP bonding technique could be regarded as first choice and favourable during orthodontic intervention, since this method consists of fewer steps than CM-AEP thus requires less time (16), and less vulnerable to errors originating from operator usage (54). But the heterogeneity of outcomes indicate that more well designed, high-quality RCTs are needed to obtain strong evidence about the relative failure risk of bonding between the SEP the CM-AEP methods.
Both SCRs and simple or resin-modified glass ionomer materials present disadvantages compared with the etching techniques. These include cumbersome preparation of cement, possible displacement of bracket from its initial position during polymerization of SCR or RM-GIC, long polymerization time, and increases in operator dependency (55). Manual mixing of materials also increases the chance of errors (e.g. introduction of voids, alteration in proportions) (56). These and the presence of better alternatives are the main reasons why both techniques were pushed into the background in the field of orthodontics. Despite of all these, these chemically cured materials are in routine use during multibond fixed appliance therapy, when no alternative techniques can be applied. As a consequence, according to a survey, SCR, and RM-GIC materials are still used routinely in 23.6 and 3.4%, respectively, in orthodontics in the UK (57). In the case of band cementation, the use of GIC-based materials is still the best available technique, as etching is not an applicable option in such cases (57). During surgical exposure of impacted or unerupted teeth, the direct bond of attachment (standard bracket, button, hook) often fails following the use of adhesive techniques (58). When the control of moisture is limited or not possible, RM-GIC could be a good technique, as it is less sensitive in a wet environment and has clinically acceptable bond strength, which increases 24 hours after application (5,57). In such cases, the direct bonding of brackets with this material is not contraindicated, reportedly yielding acceptable or comparable results to composite adhesives (59)(60)(61)(62).
In our meta-analysis, the risk of bond failure using SCR materials in comparison with GIC or resin-modified GIC was significantly lower at both 12 and 18 months after bonding. The difference in failing brackets was 6.0 and 20.8% after 12 and 18 months, respectively, representing dramatic disadvantages of RM-GIC over SCR, especially during at least one and a half year long applications. Our results are in accordance with the outcome of most individual investigations. Additionally, in vitro studies on bond strength also yielded lower values for glass ionomers than for adhesive technologies (7,63,64). Our results are substantially different from the outcome of the earlier meta-analysis by Khan et al., showing that there was no statistically significant risk difference of bracket failure between brackets bonded with RM-GIC and SCR techniques (17). The reason for the divergent results are not clear. On the other hand, similar to us, Mickenautsch et al. (15) found no difference in the failure rate between the two treatment groups after 12 months and found in favour of composite resin adhesive after more than 14 months. However, in both studies the strength of evidence was much lower compared with us, since we were able to include considerable more studies. Also, the time-dependent breakdown in forming groups seems to be very important since bracket failure increase by time, as shown by many studies including our present investigation.

Strengths of the study
An important strength of this meta-analysis is that it revealed no significant difference between SEP and CM-AEP up to 18 months after application. In addition, evidence was provided the superiority of SCR over RM-GIC was evident. Indirectly we were also able to compare CM-AEP, SEP, SCR, and RM-GIC techniques. The results clearly showed that glass ionomers had much worse failure rates compared with acid-etching methods thereby demonstrating an important message for clinicians for selecting their orthodontic bond technique. Additionally, subgroup analyses showed that in our investigation the outcomes did not depend on relatively small differences in study design.

Limitations of the study
A major limitation of the present work is that the included clinical trials, with no exceptions, showed variable levels of risk of bias. The measurable variables of bonding processes presented in the summary table, such as light-curing time, etching time, and type of etch in the case of GIC and RM-GIC, also show some grade of differences among the involved studies. Also, demographic data are not uniformly presented and were incomplete in some cases. Other factors, such as the experience of the clinician, and the eating, chewing and tooth brushing habits of the patients-which also contribute to bracket failure-are not measurable and they were obviously variable in the included studies. The wide range of publication dates and the large scale of applied dental materials also cause a considerable limitation of our work. Additionally, due to the small number of available studies, we were unable to directly conduct a meta-analysis on the comparison of both CM-AEP, SEP, SCR, and RM-GIC techniques. Subgroup analyses could not be done in all study cohorts due to the low number of studies in certain experimental designs. Although multiple studies stated the importance of cluster analysis using available methodological and statistical approaches (65), no intra-cluster coefficients were reported in the included studies.
A possible problem affecting the outcome is the difference between the clustering effects of the S-M and the P-G bracket allocation methods. The S-M design may eliminate some of the unknown confounding factors, but it may introduce carry-over effects between different sides that are being evaluated (66). According to the Cochrane Handbook, the effects of clustering could be approximated by modifying the sample size and the number of subjects with effects based on the size of the cluster and the intra-cluster coefficient (67). It is desirable to pool separately the outcome measurements of S-M and P-G studies. But unfortunately, in our meta-analysis the number of studies with P-G bracket allocation was so low that only one subgroup analysis could be performed regarding SEP versus CM-AEP, which was at 12 months.

Conclusions
Based on the results, the, null hypothesis regarding to the CM-AEP and SEP techniques has been accepted. Within the limitations of this meta-analysis, the results suggest no significant difference in bracket failure at 6, 12, and more than 18 months using the CM-AEP and SEP methods. In the case of SCR-RM-GIC techniques, the null hypothesis was rejected. The RM-GIC techniques performed worse at both the 12-and 18-month follow-up periods compared with self-cure composites. Based on our observations on bracket failure, in clinical applications lasting longer than 12 months, the CM-AEP and SEP techniques yielded three to six times better outcomes than the GIC and RM-GIC applications. Therefore, whenever it is possible, the first two techniques should be used over the latter two in clinical settings.
Supplementary Figure 1. Sensitivity analysis of bracket failures between SEP and CM-AEP after 6 months. Omitting any of the studies did not significantly alter the overall estimate.
Supplementary Figure 3. Sensitivity analysis of bracket failures between SEP and CM-AEP after more than 18 months. Omitting any of the records, did not significantly change the overall estimate.
Supplementary Figure 4. Sensitivity analysis of bracket failures between SCR and RM-GIC after 12 months. Leaving out any of the studies did not significantly change the overall estimate.
Supplementary Figure 5. Sensitivity analysis of bracket failures between SCR and RM-GIC after 18 months. Omitting any of the studies did not significantly alter the overall estimate.
Supplementary Figure 6. Funnel plot of SEP and CM-AEP after 6 months. Symmetrical funnel plot, with no signs of publication bias, Egger's test (P = 0.890) indicates no smallstudy effect.
Supplementary Figure 7. Funnel plot of SEP and CM-AEP after 12 months. Missing dots (studies) indicates more studies are needed with increased sample size and statistical power, Egger's test (P = 0.472) indicates no small-study effect.
Supplementary Figure 8. Funnel plot of SCR and RM-GIC after 12 months. Slight asymmetry of the plot indicates presence of statistical heterogeneity, however Egger's test (P = 0.129) indicates no small-study effect.